Synthesis of Novel Amide-Linked Dimers of Lithocholic Acid

Joachimiak, Roman; Piasecka, Monika; Paryzek, Z.

doi:10.3184/030823408x318325

Cited by 3 publications

(3 citation statements)

References 40 publications

(24 reference statements)

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“…The C24 amine (21), C24 amide (carbonyl at C24; 22) and a diol (23) were prepared according to literature procedures. [37,38] BK channel activation Initial modification of the LCA molecule (C24) began with the shortening and elongation of the LCA isooctyl chain attached to C17 of the steroid nucleus, rendering C24 and C25 steroids, respectively (Figure 2 a). Compounds 3 and 15 were generated and tested at 150 mm, the latter being the effective concentration causing 90 % of the maximum effect (EC 90 ) for LCA activation of b1-containing BK channels.…”

Section: Chemical Synthesismentioning

confidence: 99%

Calcium‐ and Voltage‐Gated Potassium (BK) Channel Activators in the 5β‐Cholanic Acid‐3α‐ol Analogue Series with Modifications in the Lateral Chain

Bukiya

Patil

et al. 2012

ChemMedChem

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Large conductance, calcium- and voltage-gated potassium (BK) channels regulate various physiological processes and represent an attractive target for drug discovery. Numerous BK channel activators are available. However, these agents usually interact with the ubiquitously distributed channel-forming subunit and thus cannot selectively target a particular tissue. Here, we performed structure-activity relationship study of lithocholic acid (LCA), a cholane that activates BK channels via the accessory BK β1 subunit. The latter protein highly abundant in smooth muscle but scarce in most tissues. Modifications in the LCA lateral chain length and functional group yielded two novel smooth muscle BK channel activators, both having a small volume and a net negative charge in the substituent radical at C24. Our data provide detailed structural information that will be used to advance a pharmacophore in search of β1 subunit-selective BK channel activators. These compounds are expected to evoke smooth muscle relaxation, which would be beneficial in the pharmacotherapy of prevalent human disorders associated with increased smooth muscle degree of contraction, such as systemic hypertension, cerebral or coronary vasospasm, bronchial asthma, bladder hyperactivity, and erectile dysfunction.

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Section: Chemical Synthesismentioning

confidence: 99%

Calcium‐ and Voltage‐Gated Potassium (BK) Channel Activators in the 5β‐Cholanic Acid‐3α‐ol Analogue Series with Modifications in the Lateral Chain

Bukiya

Patil

et al. 2012

ChemMedChem

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“…183 Methods for the synthesis of cholaphanes continue to be described including the use of ring-closing metathesis and palladium-catalysed amination reactions in the construction of the macrocyclic structures. [184][185][186][187] Methyl 12-(D-prolinoylamino)cholate 44 has been used 188 as an organo-catalyst for the asymmetric aldol condensation of cyclohexanone and aromatic aldehydes.…”

Section: Bile Acidsmentioning

confidence: 99%

Steroids: partial synthesis in medicinal chemistry

Hanson

2010

Nat. Prod. Rep.

102

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“…14 The synthetic approach es reported so far, have led to the preparation of cyclic and acyclic steroidal dimers, by connection between two cyclopentano-perhydrophe nanthrene skeletons (through A-A, B-B, C-C, D-D or A-D rings). [3][4][5] The steroidal moieties could be directly linked, [15][16][17] linked through spacer groups [18][19][20][21][22][23][24][25] and by connection through the steroidal side chains. [26][27][28][29] Concerning steroidal D-D ring dimers linked through spacer groups, a number of pollutant multi-step and low-yielding synthetic approaches have been frequently used.…”

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confidence: 99%

A new facile synthesis of steroid dimers containing 17,17′-dicarboxamide spacers

Carrilho

Pereira

Moreno

et al. 2013

Tetrahedron Letters

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a b s t r a c tA set of new steroid dimers linked through ring D-ring D were synthesized via catalytic diaminocarbonylation of 17-iodo-5 a-androst-16-ene, in the presence of palladium-phosphine in situ catalysts and aliphatic or aromatic diamines as N-nucleophiles. The dimeric steroidal comp ounds containing 17,17 0 -dicarboxamide spacers were obtained through highly chemoselective reactions in good isolated yields and completely characterized by spectro scopic techniques.Ó 2013 Elsevier Ltd. All rights reserved.Steroids are widely found in both plant and animal kingdoms, and play crucial roles in biological systems.1,2 Among them, dimeric steroids constitute a class of compound s, which have recently attracted much attention due to their remarkable properties as potential cytotoxic, antimalarial, anticancer, and cholesterol lowering drugs as well as molecular umbrellas in drug delivery. [3][4][5][6][7][8][9] In addition to their pharmacologic al importance, several dimeric and oligomeric steroids display micellar activity, 10 they can also act as ligands for proteins and trigger cellular processes or may promote the affinity of ligands to their binding locations by providing extra anchoring points to the active site of certain domains. 11,12 Some of the dimers show liquid-crystal behaviour 13 and play key roles in rate enhancem ent from hydrophobic binding. 3 Thus, other environmentall y sustainab le alternativ es to promote steroid dimerizatio ns still constitute a great challenge. It is well established that transition-m etal-catalyzed reactions are versatile tools to introduce different functionalities into specific positions of the steroidal framework, which can render marked changes in their biologica l properties. 30 Recently, our groups have reported several examples on the aminocarbonylation of steroidal alkenyl-iodide s toward carboxamides . 31 Nevertheless, to the best of our knowledge, there is only one example on the synthesis of dimeric steroids involving Pd-catalyzed carbonylativ e dimerization of alkenyl-iodide intermediates , to form 17-carbox ylic anhydrides, in the presence of carbon monoxide and water. 32 It should be also noted that the application of diamines as N-nucleop hiles in palladium-cata lyzed aminocar bonylation toward dicarboxamide s is unprecedented. Therefore, the iodoalkene-based catalytic synthetic strategy described herein provides a complete ly new, facile, efficient, and atom economic methodology for the preparation of steroid dimers. A set of dimeric androst-16-en es with structurally different dicarboxamide spacers at C-17 was synthesized via one-pot, one-step palladium-cata lyzed aminocar bonylation of 17-iodo-5 a-androst-16-ene (1), which was obtained by the modified Barton's procedure from the correspond ing 17-ketone. The carbonylativ e dimeriza tion reaction leading to steroidal dicarboxami des (2a-2d) took place under relatively mild conditions (30 bar CO, 100 °C), with nearly full conversion of the initial iodo alkenyl steroid in 5 h. The symmetric androst-16-en e ...

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Synthesis of Novel Amide-Linked Dimers of Lithocholic Acid

Cited by 3 publications

References 40 publications

Calcium‐ and Voltage‐Gated Potassium (BK) Channel Activators in the 5β‐Cholanic Acid‐3α‐ol Analogue Series with Modifications in the Lateral Chain

Calcium‐ and Voltage‐Gated Potassium (BK) Channel Activators in the 5β‐Cholanic Acid‐3α‐ol Analogue Series with Modifications in the Lateral Chain

Steroids: partial synthesis in medicinal chemistry

A new facile synthesis of steroid dimers containing 17,17′-dicarboxamide spacers

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